We propose to investigate why mature, central nervous system (CMS) neurons fail to regenerate after injury, and how this failure depends on the developmental control of gene expression. Mature retinal ganglion cells (RGCs) fail to regenerate after their axons are severed, yet axons in the embryonic CMS can regenerate after injury. The loss of this embryonic regenerative ability correlates with the loss of RGCs1 intrinsic ability to rapidly extend axons. Interestingly, neonatal RGCs do not decrease their axon growth ability by an intrinsic aging mechanism, but rather they are signaled to do so by amacrine cells. In this proposal we will investigate the cellular and molecular mechanism for this loss of intrinsic axon growth ability. We demonstrate that the amacrine-signaled decrease in RGC axon growth ability correlates with an increased ability to elongate dendrites, and is dependent on new gene expression in RGCs. In the first aim we will use an in vivo model in which amacrine cells largely fail to develop to ask whether amacrine cells are required for the developmental loss of intrinsic axon growth ability by RGCs. In the second aim we will characterize the amacrine cell membrane-associated cue that is sufficient to signal embyronic RGCs to decrease their axon growth ability, and use microarrays to develop a list of candidates genes. In the third aim we will use powerful transfection and RNAi techniques to investigate the molecular basis of RGCs1 decreased axon and increased dendrite growth abilities. Our goal is to revert mature, postnatal RGCs to their embryonic axon growth ability, and to enhance RGC regeneration after optic nerve injury in vivo. Our ultimate goal is to develop new treatments to promote RGC regeneration after injury in ocular diseases including glaucoma, retinal ischemia, optic neuritis and optic neuropathies, and to extend our understanding to more broadly promote CMS regeneration, for example after spinal cord injury or in neurodegenerative disease. [unreadable] [unreadable]